Genes Involved in Paternal Mitochondrial Degradation in C. elegans

参与线虫父本线粒体降解的基因

• 批准号: 6820585
• 负责人: CRAIG W LAMUNYON
• 金额: $ 12.35万
• 依托单位: CALIFORNIA STATE POLY U POMONA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6820585
• 关键词: Caenorhabditis elegans; embryology; gene expression; gene mutation; gene targeting; genetic susceptibility; health science research support; helminth genetics; immunocytochemistry; mitochondria; mitochondrial disease /disorder; mutant; nucleic acid sequence; sperm; ubiquitin

The proposed research continues a genetic investigation of mitochonddal inheritance. Mitochondria are universally inherited only from the egg, not from the sperm. Rare instances of abnormal inheritance of paternal mitochondria in humans can result in developmental problems or metabolic disorders. Recent cell biological studies have shown that mammalian sperm mitochondria are marked with ubiquitin, the universal degradation signal in eukaryotic cells. However, we do not yet know the suite of genes involved in this process, and whether this suite includes only sperm genes or both sperm and egg genes. Also, it is not clear whether non-mammalian taxa use ubiquitin for paternal mitochondrial degradation, in our previous studies with the nematode C. elegans, we have generated four mutant strains that fail to eliminate the sperm mitochondria from the embryo. These are the first such mutants ever generated in any species. The research proposed here will continue our genetic investigations of the mechanism of paternal mitochondrial destruction in C. elegans using the powerful genetic and genomic tools available for this species. Specifically, we aim to test the hypothesis that sperm mitochondria are uniquely tagged for destruction inside the embryo. We will continue our random mutagenesis for mutations that block the degradation of sperm mitochondria. Our previous mutations and new ones we isolate will be mapped and their sequence determined. We will test a second hypothesis that the oocyte actively recognizes the sperm mitochondria and degrades them. We will mutegenize and select for mutant oocytes that fail to eliminate the sperm mitochondria, and we will then map and determine the sequence of the mutated genes. Finally, we will test a third hypothesis that ubiquitin is the degradation label for sperm mitochondria. In a collaborative study, we will continue to knock out sperm specific genes that are associated with the ubiquitination pathway and examine the mutants for paternal mitochondrial inheritance. This project represents a comprehensive effort to study mitochondrial inheritance, and it provides the first genetic approach to the problem. Furthermore, identification of the genes involved in paternal mitochondrial degradation will help elucidate the mechanism of mitochondrial inheritance.

拟议的研究继续进行线粒体遗传的遗传调查。线粒体普遍只遗传自卵子，而不是精子。罕见的人类父系线粒体遗传异常的情况可能导致发育问题或代谢紊乱。最近的细胞生物学研究表明，哺乳动物精子线粒体标记有泛素，这是真核细胞中普遍存在的降解信号。然而，我们还不知道参与这一过程的基因组，以及这组基因组是否只包括精子基因或精子和卵子基因。此外，在我们以前对线虫C.在elegans中，我们已经产生了四种突变株，它们不能从胚胎中消除精子线粒体。这是有史以来在任何物种中产生的第一个这样的突变体。本研究将继续我们对C.使用强大的遗传学和基因组工具，为这个物种。具体来说，我们的目标是测试精子线粒体在胚胎内被独特地标记为破坏的假设。我们将继续我们的随机诱变突变，阻止精子线粒体的降解。我们以前的突变和我们分离的新突变将被映射，并确定它们的序列。我们将检验第二个假设，即卵母细胞主动识别精子线粒体并降解它们。我们将突变并选择那些不能消除精子线粒体的突变卵母细胞，然后我们将绘制并确定突变基因的序列。最后，我们将测试 第三个假说是泛素是精子线粒体的降解标记。在一项合作研究中，我们将继续敲除与泛素化途径相关的精子特异性基因，并检查父系线粒体遗传的突变体。该项目代表了研究线粒体遗传的全面努力，它提供了解决该问题的第一个遗传方法。此外，确定参与父系线粒体降解的基因将有助于阐明线粒体遗传机制。